Conicet Researchers Discover Mechanism for Dengue Virus 1, 2, and 3 to Disrupt Antiviral Response in Human Cells

researchers of the Conicet and the Leloir Institute Foundation (FIL) discovered a mechanism for dengue virus 1, 2 and 3 to disrupt the antiviral response of human cells, knowledge that could open the door to the design of more effective vaccines against this disease

The research, which was published this Monday in the prestigious journal Proceedings of the National Academy of Sciences (PNAS), It was led by Mora González López Ledesma and directed by the virologist Andrea Gamarnikboth Conicet researchers in the Leloir Institute Foundation.

“When the virus infects a cell, it begins to produce molecules called interferons and triggers a whole antiviral system. What we found is that there is a dengue 2 virus protein that deactivates and eliminates a protein that is important for this antiviral process,” Gamarnik explained to Télam.

And he continued: “What we verified at the molecular level is present in the dengue 2 virus, it is also in 1 and 3, but it is not in dengue 4. This difference is very important because the dengue 4 virus is the that behaves best to trigger immunity in the context of vaccines”.

Achieving a vaccine against any disease is not an easy taskbut dengue is even more complex: “Dengue disease is actually caused by four different viruses, they could have been called by different names but they were named dengue 1, 2, 3, and 4. They have similar characteristics but are also differences. So it’s like having to make 4 vaccines in 1. That makes the development of these vaccines complex,” he explained. Gamarnik, current head of the Molecular Virology Laboratory of the FIL.

She with her team They have been researching these four viruses for 20 years that produce dengue disease; in fact, the research that led to this finding began more than three years ago, but in 2020 the work was interrupted by the Covid-19 pandemic.

In mid-2022, the investigations on dengue were resumed and they made the discovery that is now published in PNAS, a journal of the National Academy of Sciences of the United States, with wide international scope.

About this finding, Gamarnik confessed to the CyTA-Leloir Agency that “we weren’t looking for what we found; in fact, if we had set our minds to it, we wouldn’t have made it because it was like finding a needle in a haystack.”

The scientist described that what they were developing was a basic research project to generate knowledge about how the proteins of the virus interact with those of the human cell. “We use proteomics technology and we were able to measure thousands and thousands of interactions. Suddenly our attention was drawn to the fact that a virus protein, called NS5, attached itself to another present in the cell and deactivated it, eliminating it. Then the question arose as to what the virus does to eliminate that cellular protein. It was thus that we entered an unexpected path of investigations that took us about three years,” recalled Gamarnik.

As Gamarnik explained to Télam, The importance of this finding lies in the fact that in the development of current vaccines it is observed that the attenuated dengue 4 viruses generate high immunity, while those of dengue 2 do not do it as well and that, now you know, is related to the discovery that you have just published: type 2 is more effective in inactivating the cell antiviral response.

“If we know the changes that we can make at the molecular level so that the type 2 virus cannot counteract the action of the immune system, we can, through genetic engineering, design better vaccines”, specified Mora González López Ledesma, first author of the publication. And he added that “in our work we found that by changing just one amino acid of the dengue 2 NS5 protein (it would be equivalent to removing a brick in the entire building of the viral protein) we can simulate what happens in dengue 4.” In other words: “An attenuated dengue 2 virus could be developed that it behaves like dengue 4, that is, that it does not deactivate the antiviral response of the cells”.

In Argentina there are currently two vaccines against dengue: the one from the Sanofi Pasteur laboratory, indicated only for people between the ages of 6 and 45 with confirmed previous dengue infection, which is currently not marketed.

And a second that is the recently authorized Takeda company, which acts against the four serotypes of dengue and will only be available in the spring.

“An important feature of the dengue virus is that prior exposure to any of the four serotypes can cause a more severe clinical manifestation if the new infection is with a variant different from the previous one. That is why it is so important to have quadrivalent vaccines equally effective against the four serotypes, something that none of the existing vaccines has yet achieved,” said the CyTA-Leloir Agency.

This season Argentina went through an outbreak with a record amount of chaos in recent years.s: according to data from the latest National Epidemiological Bulletin, Until May 20, 106,672 cases of dengue were registered of which 99,456 were autochthonous, 5,937 are under investigation and 1,279 have travel records (imported); In addition, 59 deaths were reported.

The Epidemiological Bulletin pointed out that “if the epidemic curve is compared with the two previous epidemic seasons, it is observed that from March 5 to May 6, a greater number of cases was registered; in turn, the seasonality resembles that of the one registered in 2020.

Until now, the predominant circulation of dengue 2 has been registered in the country, being identified in 81.16% of the subtyped cases; followed by dengue 1, at 18.79%; and dengue 3, in very low circulation, with 0.05%.